Stability of regulatory T cells undermined or endorsed by different type-1 cytokines

Regulatory T cells (Tregs) encompass an array of immunosuppressive cells responsible for the protection against exacerbated immune responses and the maintenance of tissue homeostasis. Various Treg subtypes, normally resident within distinct lymphoid and non-lymphoid tissues, can be recruited and expanded during inflammation, possibly undergoing functional and molecular re-programming. Generally, two processes have been reported in different settings of type-1 response: i) Treg subpopulations acquiring the ability to specifically suppress Th1 cells (called Th1-suppressing Tregs), and ii) Treg subsets rather polarizing into IFN-γ-producing (called Th1-like) Tregs. Along the development of type-1 responses, Tregs are exposed to a variety of cytokines and other signals, exerting disparate activities. The combinatorial effects of typical Th1-driving cytokines, such as IL-12 (mostly produced by antigen-presenting cells during Th1 priming) and IFN-γ (mostly produced by pre-existing NK cells) lead to inhibition of Treg expansion and function, while promoting Th1-like Treg polarization. Conversely, cytokines produced at more advanced phases by Th1 effectors, such as IL-2, TNF-α and IFN-γ, promote Treg proliferation and/or Th1- suppressing Treg specialization. Some controversy exists around IL-27 and IFN-α, cytokines possibly released during bacterial or viral infections. Furthermore, cytokine signals can be finely tuned by the concomitant stimulation of costimulatory or coinhibitory receptors, such as OX40 and PD-1 respectively, within inflamed tissues. A model may be envisaged of an alternate Treg response to type-1 cytokines, being hampered or boosted by early or late phase cytokines, respectively. Such regulation would unleash the development of protective type-1 immunity while constraining exacerbated Th1 responses, possibly causing immunopathology.